Within the past ten years scientists have begun characterizing complex strains of multiple drug resistant (MDR) falciparum malaria which are increasing at an alarming rate both in terms of prevalence and severity. Also, chloroquine resistance in vivax malaria has been detected. As the utility of current drugs continues to diminish, health-care providers in and outside the United States will see many more cases of malaria. The purpose of the proposed study is to identify new antimalarial chemotypes for development into orally-active, safe and effective drugs. Antimalarial activity, toxicity and mutagenicity of medicinal plants derivatives will be evaluated using in vitro and in vivo models. The Associate Program on Antimalarial Drug Discovery and Development involves a sequences of specific in vitro tests designed to restrict the number of in vivo tests. Initial ethnopharmacological information and data on two preliminary assays-potato disc and brine shrimp will precede the antimalarial tests. In vitro radioscope uptake assay for antimalarial activity against Plasmodium falciparum drug sensitive and resistant clones will be performed.) The approaches used by the WRAIR program have involved empirical screening, screening of plant extracts from traditional medicines, synthesis of analogs of compounds known to have antimalarial activity and selective targeting at specific parasite enzymes.